Hepatitis C virus (HCV) is highly prevalent in Japan, which provides an ideal situation for its study. In a cohort study, the interactions of HCV and human T lymphotropic virus type I (HTLV-I) were studied in an area of Japan where both viruses were endemic. Liver cancer death was highly associated with antibody to HCV (anti-HCV). Antibody to HTLV-I (anti-HTLV-I) was somewhat correlated with HCV infection, but provided no added risk for liver cancer. In a related study, a cohort of Japanese Americans in Hawaii was studied; all were descended from persons who had emigrated from Japan before the mid-twentieth century epidemic of HCV in Japan. A strong association between hepatocellular carcinoma (HCC) and hepatitis B virus (HBV) was found in this population, but not between HCC and HCV; this differs from the situation in Japan today, where 80% of HCC patients have HCV infection.Studies were conducted in HCCs from the United States to determine whether DNA mismatch repair defects could play a role. Microsatellite instability was detected in 4 of 10 HCCs. The one HCC patient with multiple p53 exon mutations had microsatellite instability; five patients with multiple p53 intron alterations in the HCC (compared to their own nontumorous livers) had no microsatellite instability. Mismatch repair defects resulting in microsatellite instability might have played a role in hepatocarcinogenesis in four of these patients, but it was unrelated to p53 alterations in three of them.